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J L Dhondt

Publications and source records attributed to J L Dhondt.

At least 19 recordsLinked to original sources
PubMed1996

Need for a standardized procedure in the preparation of phenylalanine calibrators.

INTRODUCTION: Sensitive screening for phenylketonuria (PKU) and other disorders requires accurate measurement of analytes in blood eluted from filter paper. The development of new quantitative methods for phenylalanine measurement in dried blood spots for PKU screening has introduced an increased number of calibrators provided with the kits. We compared the phenylalanine values of seven different sets of calibrators (six from commercial sources and one from a screening laboratory), all measured with the same technique. METHODS: Two types of filter papers, S&S #903 and S&S #2992 were used. Phenylalanine was measured by high performance liquid chromatography (HPLC). RESULTS: There was a wide variation in the phenylalanine values assigned to the seven different sets of calibrators used, with the ratios of HPLC to assigned value ranging from 0.68-1.62. This could not be only explained by the use of different types of filter papers. However, factors in calibrator preparation did influence the measured concentration. These included higher values when 100 microliters rather than 35 microliters of blood was spotted, when the red blood cells were intact rather than lysed, and as the hematocrit increased. DISCUSSION: These observations emphasize the need to establish recommendations for preparation of dried blood calibrators in order to appropriately compare new techniques and exchange screening experiences among centers.

Calibration↗
PubMed1996

International database of tetrahydrobiopterin deficiencies.

Approximately 2% of newborns with hyperphenylalaninaemia are deficient in tetrahydrobiopterin. Selective screening must be performed in all instances where hyperphenylalaninaemia is detected by neonatal screening. In the last 20 years, 308 patients with tetrahydrobiopterin deficiencies have been recognized as a result of screening carried out, worldwide, in Departments of Paediatrics. Of these 308 patients, 181 suffered from 6-pyruvoyltetrahydropterin synthase deficiency, 92 from dihydropteridine reductase deficiency, 13 from pterin-4a-carbinolamine dehydratase deficiency, 12 from GTP cyclohydrolase I deficiency, and 10 are still unclassified. In the BIODEF database we have tabulated the most common clinical and laboratory data related to hyperphenylalaninaemia and tetrahydrobiopterin deficiencies. Additionally, there are data regarding treatment, outcome, and DNA analysis. Preliminary evaluation reveals that the degree of hyperphenylalaninaemia can vary from normal to 2500 mumol/L. Analyses of pterins in urine and measurement of dihydropteridine reductase activity from Guthrie cards are absolutely essential tests for accurate diagnosis. There is a regional (demographic) variation in the frequency of tetrahydrobiopterin deficiencies indicating the highest incidence in Saudi Arabia, probably a consequence of the high consanguinity rate.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Population-based differences in thyrotropin and thyroxine distributions in healthy newborns revealing results from independent reagent evaluation.

An independent evaluation of reagents for the determination of thyroxine and thyrotropin from dried blood spot samples taken from newborns between the third and fifth day of life revealed striking differences in the thyrotropin distribution among newborns from Byelorussia. An analysis of the thyrotropin distribution from Byelorussian newborns showed that 40% of samples had over 5 mIU/l blood. In other European populations comparable in respect to timing of blood collection, this fraction varied from only 1% (Stockholm, Sweden) to 3.7% (Lille, France). The reason for the "shift right" in Byelorussian newborns remains to be further investigated. This shift can be attributed to the synergetic effects of mild-moderate iodine deficiency and/or as yet unidentified environmental factors. The differences observed in cumulative distribution patterns obtained by two commercial methods question the use of absolute figures (such as the proportion of samples over 5 mIU/l) for the purpose of inter-population comparisons.

France↗
PubMed1995

Changes of cerebral biopterin and biogenic amine metabolism in leukemic children receiving 5 g/m2 intravenous methotrexate.

Acute or subacute neurologic disorders can be observed in patients receiving high-dose methotrexate therapy for lymphoblastic leukemia or malignant tumor. Impairment of biopterin metabolism leading to decreased availability of monoamine neurotransmitters has been suggested to explain methotrexate neurotoxicity. To investigate such a mechanism, we have measured prospectively by HPLC the concentrations of total biopterin, homovanillic acid, and 5-hydroxyindolacetic acid in cerebrospinal fluid of 57 children with acute lymphoblastic leukemia. A sequential analysis of cerebrospinal fluid was performed for each patient: cerebrospinal fluid samples were obtained before therapy and after each of the four high-dose methotrexate infusions during the CNS prophylaxis phase. A significant increase of total biopterin concentrations in cerebrospinal fluid was observed after high-dose methotrexate therapy compared with the pretreatment values. No cumulative effect was noted. In contrast, no significant variation of the homovanillic acid and 5-hydroxyindolacetic acid levels was observed in cerebrospinal fluid. However, individual analysis revealed a transient decrease of homovanillic acid and 5-hydroxyindolacetic acid concentrations in cerebrospinal fluid of six children. The increase of total biopterin mimicking that observed in inherited dihydropteridine reductase deficiencies suggests that methotrexate inhibits the regenerating system of biopterin in the brain of patients undergoing high-dose methotrexate therapy.

Adolescent↗
PubMed1995

[Epidemiological data. Neonatal and prenatal screening].

Unlike what is generally thought, cystic fibrosis is not the most frequent hereditary disease. Its frequency is approximately 1/3 200 and varies with the geographic area. The frequency of heterozygous subjects is about 1/28. No country has established a generalized neonatal screening programme, for technical reasons and because there has been no demonstration of a beneficial effect from early care. It would nevertheless be useful to develop experimental programmes defining which protocols might best be established. Antenatal screening can be based on detecting heterozygous subjects, a technically feasible operation, although answers to a large number of questions would be required.

Cystic Fibrosis↗
PubMed1993

2,4-diamino-7-hydroxy-pteridines in biological fluids of patients on high-dose methotrexate.

Concentrations of 2,4-diamino-7-hydroxy-pteridines in plasma and cerebrospinal fluid (CSF) are reported for the 0.5-8 g/m2 dose range of methotrexate in children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma. This experiment has revealed that: (1) there is a wide inter-individual but relatively narrow intra-individual variability of the maximal concentrations of 2,4-diamino-7-hydroxy-pteridines in plasma during consecutive methotrexate cycles; (2) the increase in the level of the metabolites in plasma was related to increments of the methotrexate dose, but not above 5 g/m2: this can be explained by a saturable conversion of methotrexate to 2,4-diamino-7-hydroxy-pteridines; (3) significant correlations were found between simultaneous values of 2,4-diamino-7-hydroxy-pteridines in plasma and CSF; (4) the formation of 2,4-diamino-7-hydroxy-pteridines did not depend on the ages of patients receiving the same dose of methotrexate. The presence of these compounds in plasma and CSF in significant amounts creates the potential for a number of competitive interactions with pteridine-dependent metabolism which may open up new possibilities for understanding the metabolic side-effects of methotrexate therapy.

Adolescent↗
PubMed1993

Cerebrospinal fluid neopterin levels in children with central nervous system leukemia.

Cerebrospinal fluid (CSF) neopterin levels were determined by high-pressure liquid chromatography in 48 normal children and in 15 children with meningeal relapse of hematologic malignancies (13 acute lymphoblastic leukemia and 2 high-grade lymphomas). When meningeal relapse was diagnosed, all patients had CSF neopterin levels higher than mean normal value +2 standard deviations. No significant correlation between the blast count in the CSF and neopterin levels was observed. CSF data before relapse were available in 10 children: the neopterin values at relapse were significantly higher than values observed at diagnosis. In 3 patients, elevated neopterin levels preceded the occurrence of neurologic signs and the detection of blast cells in CSF by 15 to 30 days. In the absence of infection, the rise of CSF neopterin levels in patients with hematologic malignancies indicates an active phase of the disease. This could reflect a cell-mediated immunologic process induced by malignant cells. The measurement of CSF neopterin should be helpful in the monitoring of patients to detect early meningeal relapse.

Adolescent↗
PubMed1993

[Unconjugated pteridines and neuromeningeal infections].

Concentrations of unconjugated pteridines (neopterin, monapterin, biopterin, pterin) were measured in the cerebrospinal fluid (CSF) of 310 patients, using a high performance liquid chromatography (HPCL) method. Our cohort included 209 controls (C), 15 patients with meningism (M), 22 with viral meningitis (VM), 17 with bacterial meningitis (BM), 9 with herpetic meningoencephalitis (HME), 2 with tuberculous meningoencephalitis (TME) and 36 with peripheral systemic infections (PI). These measurements, expressed as nmol/litre, showed a gradation of neopterin concentrations according to the type of infection: 20.1 + 6.5 in group C; 46.9 +/- 29.9 in group PI; 274.3 +/- 231.7 in group VM; 699.2 +/- 711.2 in group BM, 1,101.9 +/- 1,107.9 in group HME and 1,169 +/- 1,171.9 in group TME. There was no such gradation with biopterin. Comparisons of means showed that total concentrations in the pathology groups were very different from those observed in controls and in the neuromeningeal infections of the PI group. There was no correlation between the number of lymphocytes and the concentrations of neopterin or biopterin in the CSF. It is concluded that the concentration of neopterin in the CSF is a sensitive but little specific marker of infection, independent of CSF cellular reaction. Measuring this concentration makes it possible: 1) to evaluate the status of immune defences; 2) to predict that a meningitis will become chronic, and 3) to detect a possible parenchymal participation in a meningeal infection.

Biomarkers↗
PubMed1993

[Embryofetopathy of the newborn infant of a phenylketonuric mother. A diagnosis not to be missed].

Children with phenylketonuria (PKU) detected in the neonatal period and who have received the appropriate diet develop normally whatever their sex. However, female PKU patients who, before becoming pregnant, do not take the precaution to follow a diet bringing phenylalanine to "normal levels" (2 to 5 mg in 100 ml of blood) give birth to children presenting with severe embryofoetal damage (e.g. intrauterine growth retardation, microcephaly, mental retardation, various malformations) directly due to their hyperphenylalaninaemia (20 mg or more in 100 ml of blood under a free diet). It is important to know these facts, since the benefits of systematic neonatal PKU detection may be cancelled by this late complication. The therapeutic approach in such cases is a follows: 1. Young women with known PKU must be informed of this risk and how it can be avoided by a preconception therapeutic diet. This means that they must permanently reside in the same geographical area, receive an adequate information at the end of puberty, use and effective contraception method and program their pregnancies preceded by a return to low phenylalanine diet. 2. Doctors must remember that because PKU detection has not become systematic until 1978, PKU girls of child-bearing are remain undetected, that they are not always mentally debilitated and can normally five birth to children with embryofoetal damage. In case of e.g. unexplained intrauterine growth retardation or microcephaly, it is necessary to perform a Guthrie test on the woman, since a prenatal diagnosis may lead to therapeutic abortion, and a postnatal diagnosis to a genetic counselling which will avoid recurrences.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Impairment of cerebral biogenic amine synthesis in a patient receiving high-dose methotrexate.

A transient acute neurologic syndrome occurred in a 15-year-old boy receiving high-dose methotrexate (MTX) for acute lymphoblastic leukemia. Cerebrospinal fluid analysis revealed a decrease of homovanillic acid and 5-hydroxyindoleacetic acid concentrations with a rise of biopterin levels. These findings suggest that MTX can induce a transient alteration of the metabolism of tetrahydrobiopterin leading to the defect of biogenic amine neurotransmitter synthesis.

Adolescent↗
PubMed1992

[Measurement of dihydropteridine reductase activity in dried blood eluates: physiological and pathological implications].

Tetrahydrobiopterin deficiency in hyperphenylalaninemic babies has to be rapidly recognized since the disease requires a specific treatment. Although the measurement of pteridines in urine can detect most of tetrahydrobiopterin deficiencies, DHPR measurement has to be performed to circumvent the risk of missing DHPR deficiency, especially at the neonatal period. The possibility to measure DHPR activity in dried blood samples justifies itself by its convenience and simplicity. Expression of activity per mg of hemoglobin improves the precision of the assay by removing variation in the elution step (insufficient blood being loaded onto the filter paper, hematocrit variation, thickness of filter paper used). The distribution of DHPR activities, corrected from the progressive decrease with age, showed that 2.5% of the hyperphenylalaninemic or normal population have low levels of activity (below 50% of normal). This observation suggests that genetic variations may exist, as illustrated by the analysis of 11 families. Although blood DHPR measurement seems efficient for screening DHPR deficiency, the finding in a family of clinically normal subjects with zero activity illustrates the risk of false positive results of the enzymatic test.

Adolescent↗
PubMed1991

2,4-diamino-7-hydroxy-pteridines, a new class of catabolites of methotrexate.

Methotrexate remains a commonly used drug in the chemotherapy of various malignancies. The known catabolites are 7-hydroxy-methotrexate, formed in the liver, and diamino-methyl-pteroic acid formed in the gut. We report for the first time evidence that 2,4-diamino-7-hydroxy-pteridine derivatives are present in the biological fluids of patients on high-dose methotrexate protocols. So far, two major derivatives have been identified as 2,4-diamino-6-hydroxymethyl-7-hydroxy-pteridine and 2,4-diamino-6-methyl-7-hydroxy-pteridine. In regard to the actual knowledge of the catabolism of pteridines, these compounds are presumably formed by intestinal bacteria during enterohepatic circulation of the drug. Their slow clearance from the body raises the question of possible interference of these compounds on pteridine-dependent enzymes, which might explain in part some of the toxic effects of methotrexate.

Adolescent↗
PubMed1991

Economic evaluation of cost-benefit ratio of neonatal screening procedure for phenylketonuria and hypothyroidism.

A comparison between the cost of identification and care of patients with phenylketonuria (PKU) and congenital hypothyroidism (CH) and the expenditure for the care of untreated retarded patients has been established on the basis of the activity of the Nord-Pas-de-Calais regional screening centre and of interviews with patients' families. The analysis yields a benefit-cost ratio of 6.6 for PKU and 13.8 for CH prophylaxis. However, cost-benefit varies depending on the economic partner, i.e. the patient's family, Social Security or Administration.

Cost-Benefit Analysis↗
PubMed1991

Strategy for the screening of tetrahydrobiopterin deficiency among hyperphenylalaninaemic patients: 15-years experience.

Tetrahydrobiopterin deficiency in hyperphenylalaninaemic babies has to be rapidly recognized since the disease requires a specific treatment. Based on 15 years experience, we report on the evolution of a strategy for the detection of such patients. A total of 913 hyperphenylalaninaemic patients have been studied and 15 tetrahydrobiopterin deficiencies have been detected or confirmed. DHPR assay in dried blood samples and pteridine measurement in urine collected on filter paper combine convenient sampling and reliable tests for systematic investigation of hyperphenylalaninaemic patients for cofactor deficiency.

Belgium↗